Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
INJECTABLE COMPOSITION
Technical Field
The present invention relates to an injectable
composition containing a benzimidazole compound such as
lansoprazole having an anti-ulcer action, and a method of
its use.
Background Art
As injectable compositions comprising a 2-[(2-
pyridyl)methylsulfinyl]benzimidazole compound having an
anti-ulcer action, for example, the following injectable
compositions have been reported.
1) JP 2-138213 A (EP 0356143 A) discloses an
injectable composition which comprises a benzimidazole
compound having an anti-ulcer action and at least one of
ethanol, propylene glycol and polyethylene glycol. The
literature also discloses an injectable solution which
contains a freeze-dried product of the benzimidazole
compound dissolved in a mixture of an acidic substance and
a polyethylene glycol, and further contains a saccharide
such as mannitol and N-methylglucamine.
2) JP 2002-128675 A (EP 1310252 A) discloses an
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injectable composition using a strong alkali in a molar
ratio of 1:1 relative to 2-[(2-
pyridyl)methylsulfinyl]benzimidazole compound having an
anti-ulcer action so that the amount of an alkali to be
used is as small as possible, that a pain or a local
irritation are suppressed, that the kneading operation and
the complicated dissolving operation are not required, that
the composition can be dissolved by a simple operation, and
further that it is not necessary to attach any specific
solution just for dissolving the injectable composition.
An injectable composition containing 2-[(2-
pyridyl)methylsulfinyl]benzimidazole compound is used for
the therapy by dissolving the composition in physiological
saline or 5o glucose solution, or the like, followed by the
intravenous injection. In that case, as a container for an
infusion solution, nowadays, a plastic container is in a
main use, though previously, a glass container was
predominantly used. The plastic container includes a
container made of a polyethylene, a polypropylene, etc. as
a hard type, a container made of these materials as
comparatively soft type and a container made of polyvinyl
chloride, a container made of a copolymer of ethylene and
vinyl acetate, etc. as a soft type. It is known that
various plastic containers contain different additives such
as a mold releasing agent, catalyst, etc., which are added
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when manufactured according to the manufacturer. European
pharmacopoeia provides for the material of a plastic
container for an injectable infusion that the concentration
of the ion of metal such as aluminum, zinc, titanium, etc,
eluted after 100 g of the material of a plastic container
has been boiled and refluxed with hydrochloric acid for one
hour is not more than 1 ppm. However, no similar provision
exists in U.S.A., and it is recognized that in a part of an
infusion container among such containers marketed in the
world, the amount of the elution of the metal ion is large.
Disclosure of the Invention
The object of the present invention is to provide a
high-quality injectable composition, comprising 2-[(2-
pyridyl)methylsulfinyl]benzimidazole compound, which is
more excellent in stability and solubility, and further is
free from formation of particulate insolubles, even when
the injectable composition is kept and supplied in a
plastic container as well as in a glass container.
The present inventors have studied intensively to
solve the above problems, and found that the formation of
particulate insolubles from metal ions eluted from a
plastic container and 2-[(2-
pyridyl)methylsulfinyl]benzimidazole compound can be
controlled by using edetic acid or its salt in a weight
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ratio of about 0.03 o to about 67 0, preferably about 0.3
to about 33 0, more preferably about 0.6 o to about 6.7 °s
relative to the active ingredient, particularly
lansoprazole, its optically active compound or a salt
thereof, and that the injectable composition containing a
benzimidazole compound can be filled in a plastic bag such
as an infusion bag or plastic vial, kept therein and
supplied therefrom. The present inventors have further
studied based on the above findings and accomplished the
present invention.
That is, the present invention relates to:
(1) An injectable composition comprising a
combination of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole),
its optically active compound or a salt thereof, and a
chelating agent, which is used at pH 9 to 12;
(2) The injectable composition according to the above
(1), which comprises a strong alkali in an amount of about
1 to about 3 equivalent relative to one mol of lansoprazole
or its optically active compound;
(3) The injectable composition according to the above
(2), which further comprises N-methylglucamine;
(4) The injectable composition according to the above
(3), wherein the amount of N-methylglucamine is about 0.1
mg to about 1 mg relative to 1 mg of lansoprazole, its
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optically active compound or a salt thereof;
(5) An injectable composition comprising a solution
of lansoprazole, its optically active compound or a salt
thereof and a chelating agent, which is substantially free
5 of insolubles and filled in a container, and which is used
at pH 9 to 12;
(6) The injectable composition according to the above
(5), wherein lansoprazole, its optically active compound or
a salt thereof, and the chelating agent are separately
stored and kept, and they are mixed at the time of using
the composition;
(7) The injectable composition according to the above
(5), which is filled in a plastic container made of a
polyethylene, a polypropylene, a copolymer of polyethylene
and polypropylene, a polyvinyl chloride, a copolymer of
ethylene and vinyl acetate, a copolymer of ethylene and
propylene, a silicone, a polybutadiene, a thermoplastic
elastomer, Teflon (Registered Trade Mark), a polyurethane,
a cyclic polyolefin or a polyolefin;
(8) The injectable composition according to the above
(1), wherein the chelating agent is edetic acid or its salt
or a derivative thereof; phosphoric acid or its salt; or
citric acid or its salt;
(9) The injectable composition according to the above
(1), wherein the chelating agent is a sodium salt of edetic
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acid;
(10) The injectable composition according to the above
(1), wherein edetic acid or its salt is contained as the
chelating agent in an amount corresponding to about 0.03
to about 67 % by weight relative to lansoprazole, its
optically active compound or a salt thereof;
(11) The injectable composition according to the above
( 1 ) , which has pH of about 10 . 4 to about 12 . 0, when it is
dissolved in a physiological saline or distilled water for
injection in a proportion of 5 ml thereof relative to 30 mg
of lansoprazole, its optically active compound or a salt
thereof;
(12) The injectable composition according to the above
(1), which is a freeze-dried preparation;
(13) The injectable composition according to the above
(1), which further comprises a saccharide;
(14) The injectable composition according to the above
(13), wherein the saccharide is a sugar alcohol;
(15) The injectable composition according to the above
(13), wherein the saccharide is mannitol;
(16) The injectable composition according to the above
(13), wherein the saccharide is contained in a proportion
of about 0.1 mg to about 20 mg relative to 1 mg of
lansoprazole, its optically active compound or a salt
thereof;
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(17) The injectable composition according to the above
(1), which contains about 3 mg to about 10 mg of sodium
hydroxide, about 8 mg to about 24 mg of N-methylglucamine,
about 50 mg to about 70 mg of mannitol and about 0.009 mg
to about 20.1 mg of disodium edetate relative to 30 mg of
lansoprazole, its optically active compound or a salt
thereof;
(18) An injectable composition which is prepared by
adding an aqueous or a non-aqueous solvent containing
edetic acid or its salt to a freeze-dried injectable
preparation containing 30 mg of lansoprazole, its optically
active compound or a salt thereof, about 3 mg to about 10
mg of sodium hydroxide, about 8 mg to about 24 mg of N-
methylglucamine and 60 mg of mannitol;
(19) The injectable composition according to the above
(1), which is for preventing or treating peptic ulcer,
gastroesophageal reflux disease; gastritis; Zollinger-
Ellison disease syndrome; NUD (Non Ulcer Dyspepsia);
gastric cancer; gastric MALT lymphoma; upper
gastrointestinal hemorrhage due to gastric ulcer, duodenal
ulcer, acute gastroduodenal ulcer and acute gastric mucosal
lesion, ulcer caused by a nonsteroidal anti-inflammatory
agent; hyperacidity and ulcer due to postoperative stress;
upper gastrointestinal hemorrhage due to invasive stress;
gastritis atrophicans after operation of endoscopic
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demucosation against early gastric cancer; hyperplastic
polyp; idiopathic thrombocytopenic purpura; a disease due
to Helicobacter pylori; asthma due to gastric acid reflux,
sleep disorder due to gastric acid reflux; abdominal pain
due to GERD; Laryngitis; chronic obstructive pulmonary
disease (COPD); obstructive apneusis; and Barrett's
esophagus;
(20) A method for preventing or treating peptic ulcer,
gastroesophageal reflux disease; gastritis; Zollinger-
Ellison disease syndrome; NUD (Non Ulcer Dyspepsia);
gastric cancer; gastric MALT lymphoma; upper
gastrointestinal hemorrhage due to gastric ulcer, duodenal
ulcer, acute gastroduodenal ulcer and acute gastric mucosal
lesion, ulcer caused by a nonsteroidal anti-inflammatory
agent; hyperacidity and ulcer due to postoperative stress;
upper gastrointestinal hemorrhage due to invasive stress;
gastritis atrophicans after operation of endoscopic
demucosation against early gastric cancer; hyperplastic
polyp;idiopathic thrombocytopenic purpura; a disease due to
Helicobacter pylori; asthma due to gastric acid reflux,
sleep disorder due to gastric acid reflux; abdominal pain
due to GERD; Laryngitis; chronic obstructive pulmonary
disease (COPD); obstructive apneusis; and Barrett's
esophagus, which comprises administering the injectable
composition according to the above (1) to a human being;
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and
(21) Use of the injectable composition according to
the above (1) for preventing or treating peptic ulcer,
gastroesophageal reflux disease; gastritis; Zollinger-
Ellison disease syndrome; NUD (Non Ulcer Dyspepsia);'
gastric cancer; gastric MALT lymphoma; upper
gastrointestinal hemorrhage due to gastric ulcer, duodenal
ulcer, acute gastroduodenal ulcer and acute gastric mucosal
lesion, ulcer caused by a nonsteroidal anti-inflammatory
agent; hyperacidity and ulcer due to postoperative stress;
upper gastrointestinal hemorrhage due to invasive stress;
gastritis atrophicans after operation of endoscopic
demucosation against early gastric cancer; hyperplastic
polyp; idiopathic thrombocytopenic purpura; a disease due
to Helicobacter pylori; asthma due to gastric acid reflux,
sleep disorder due to gastric acid reflux; abdominal pain
due to GERD; Laryngitis; chronic obstructive pulmonary
disease (COPD); obstructive apneusis; and Barrett's
esophagus.
As the active ingredient used in the present invention,
lansoprazole, that is, 2-[[[3-methyl-4-(2,2,2-
trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-
benzimidazole is preferable.
The active ingredient may be an optically active
compound of lansoprazole such as R-form and S-form of
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lansoprazole. Particularly, an optically active compound
such as (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl]sulfinyl]-1H-benzimidazole is preferable.
The active ingredient may also be a salt of lansoprazole or
5 its optically active compound.
The injectable composition of the present invention is
characterized in that it utilizes a combination of the
above active ingredient and a chelating agent. The
chelating agent may be formulated with the active
10 ingredient and, if necessary, other ingredients) in a
preparation. Alternatively, the chelating agent may be
stored and kept separately from a preparation containing
the active ingredient and these are mixed to prepare an
injectable composition at the time of using the composition.
As the chelating agent, for example, edetic acid, its salt,
a derivative thereof, phosphoric acid, its salt, citric
acid, its salt, etc. may be mentioned. These chelating
agents can be used alone or in combination. Particularly,
edetic acid and its salt are preferable. For example, an
injectable composition which contains edetic acid or its
salt in a weight ratio of about 0.03 % to about 67 0,
preferably about 0.3 o to about 33 %, more preferably about
0.6 °s to about 6.7 o relative to lansoprazole, its active
compound or a salt thereof, is free from the formation of
particulate insolubles even in case where the composition
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is filled in a plastic container, thereby permitting the
provision of a high-quality injectable composition. As a
preferable salt of edetic acid, there may be mentioned a
salt with sodium or calcium, a combination thereof, etc.
In other words, a sodium salt, a calcium salt, a salt with
sodium and calcium of edetic acid (calcium disodium edetate,
etc.), etc. are preferable. In particular, sodium salts of
edetic acid such as are more preferable, and disodium
edetate is particularly preferable. Usually, edetic acid
or its salt may be used in a weight ratio of about 0.03
to about 67 % relative to lansoprazole, its optically
active compound or a salt thereof.
In the injectable composition of the present invention
which comprises a combination of lansoprazole, its
optically active compound or a salt thereof, and a
chelating agent, the chelating agent forms a complex
compound with a metal ion eluted from a container for an
infusion solution, etc. to inhibit particulate insolubles
of the metal ion eluted and lansoprazole. Therefore, the
present invention includes an injectable composition
comprising lansoprazole, its optically active compound or a
salt thereof, and a chelating agent.
As the container for the injectable composition,
various containers such as glass containers, plastic
containers, etc. can be used regardless of their materials.
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As the plastic material for the container, a polyethylene,
a polypropylene, a copolymer of polyethylene and
polypropylene, a polyvinyl chloride, a copolymer of
ethylene and vinyl acetate, a copolymer of ethylene and
propylene, a silicone, a polybutadiene, a thermoplastic
elastomer, Teflon (Registered Trade Mark), a polyurethane,
a cyclic polyolefin or a polyolefin can be used.
In the injectable composition of the present invention,
lansoprazole, its optically active compound or a salt
thereof may be contained together with a chelating agent in
the same container. Alternatively, they may be separately
filled in different containers and mixed with each other at
the time of using the composition. Further, lansoprazole,
its optically active compound or a salt thereof is enclosed
in one partition of an infusion bag whose inside is
separated into two partitions, and an infusion solution is
enclosed in the other partition, and the chelating agent or
its salt may be enclosed in either of the two partitions.
Lansoprazole, its optically active compound or a salt
thereof may be formulated to a preparation in a liquid form
or a preparation in a solid form such as freeze-dried
injectable preparation or a powdery injectable preparation.
The solid injectable preparation can be dissolved in or
diluted with a solvent which substantially free from a non-
aqueous solvent.
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Usually, the injectable composition of the present
invention can be dissolved in or diluted with a solvent
which substantially free from any non-aqueous solvent (or a
water-soluble organic solvent) and whose medium is
substantially water by incorporating a strong alkali in
addition to lansoprazole, its optically active compound or
a salt thereof and a chelating agent in the injectable
composition. The strong alkali is used in such an amount
that the composition is used at pH about 9 to about 12, and
the ratio of the strong alkali to be used is usually about
1 to about 3 equivalents relative to one mole of
lansoprazole, its optically active compound or a salt
thereof, though it varies depending on the kind and amount
of chelating agent used.
Preferably, when lansoprazole, its optically active
compound or a salt thereof, and a chelating agent are
dissolved by using 5 ml of physiological saline or
distilled water for injection relative to 30 mg of
lansoprazole, its optically active compound or a salt
thereof, the resultant solution has pH of about 9 to about
12, preferable about 10.4 to about 12Ø
The injectable composition of the present invention
may further contain N-methylglucamine so as to suppress the
pH lowering and to stabilize the solubility when an
injectable solution is prepared. The amount of N-
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methylglucamine to be incorporated may be about 0.1 mg to
about 1 mg relative to 1 mg of lansoprazole, its optically
active compound or a salt thereof. Further, the injectable
composition may contain a saccharide (e. g. a sugar alcohol
such as mannitol, etc.) so as to stabilize a shape when the
composition is prepared in a solid form. The amount of the
saccharide to be incorporated may be about 0.1 mg to about
20 mg relative to 1 mg of lansoprazole, its optically
active compound or a salt thereof. Examples of the
injectable composition containing these ingredients include
a composition comprising lansoprazole, its optically active
compound or a salt thereof, which can be dissolved in or
diluted with a solvent substantially free from a non-
aqueous solvent, and may contain about 0.1 mg to about 0.8
mg of N-methylglucamine and about 1 mg to about 10 mg of a
sugar alcohol relative to about 1 mg of lansoprazole, its
optically active compound or a salt thereof.
Moreover, the injectable composition preferably
contains each ingredient in such a ratio as about 0.009 mg
to about 20.1 mg of disodium edetate, tetrasodium edetate,
calcium disodium edetate or a mixture thereof, about 8 mg
to about 24 mg of N-methylglucamine, about 50 mg to about
70 mg of mannitol and about 3 mg to about 10 mg of sodium
hydroxide relative to 30 mg of lansoprazole, its optically
active compound or a salt thereof. In the above case,
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disodium edetate, tetrasodium edetate and calcium disodium
edetate may be enclosed in a container different from that
containing other ingredients.
Usually, the injectable composition of the present
5 invention substantially free from a non-aqueous solvent (or
aqueous organic solvent) and can be dissolved in or diluted
with a solvent whose medium is substantially water.
Further, the injectable composition of the present
invention may be a freeze-dried preparation containing each
10 ingredient in such a ratio as about 0.009 mg to about 20.1
mg of disodium edetate, tetrasodium edetate, calcium
disodium edetate or a mixture thereof, about 8 mg to about
24 mg of N-methylglucamine, about 50 mg to about 70 mg of
mannitol and about 3 mg to about 10 mg of sodium hydroxide
15 relative to 30 mg of lansoprazole, its optically active
compound or a salt thereof. In this case, disodium edetate,
tetrasodium edetate and calcium disodium edetate may be
enclosed in a container different from that containing
other ingredients. The injectable composition can be
dissolved in at least one of liquids or solvents selected
from the group consisting of an infusion solution such as
an water for injection (distilled water for injection), an
electrolytic solution (physiological saline), a nutrient
infusion, etc. and can easily be prepared into an
injectable solution. As the container, a glass container
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and a plastic container can be used.
The present invention is useful as a method for
preventing or treating peptic ulcer, gastroesophageal
reflux disease; gastritis; Zollinger-Ellison disease
syndrome; NUD (Non Ulcer Dyspepsia); gastric cancer;
gastric MALT lymphoma; upper gastrointestinal hemorrhage
due to gastric ulcer, duodenal ulcer, acute gastroduodenal
ulcer and acute gastric mucosal lesion, ulcer caused by a
nonsteroidal anti-inflammatory agent; hyperacidity and
ulcer due to postoperative stress; upper gastrointestinal
hemorrhage due to invasive stress; gastritis atrophicans
after operation of endoscopic demucosation against early
gastric cancer; hyperplastic polyp; idiopathic
thrombocytopenic purpura; a disease due to Helicobacter
pylori; asthma due to gastric acid reflux, sleep disorder
due to gastric acid reflux; abdominal pain due to GERD;
Laryngitis; chronic obstructive pulmonary disease (COPD);
obstructive apneusis; and Barrett's esophagus, by
administering the injectable composition to a human being.
Further, the present invention also discloses use of
the injectable composition for preventing or treating
peptic ulcer, gastroesophageal reflux disease; gastritis;
Zollinger-Ellison disease syndrome; NUD (Non Ulcer
Dyspepsia); gastric cancer; gastric MALT lymphoma; upper
gastrointestinal hemorrhage due to gastric ulcer, duodenal
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ulcer, acute gastroduodenal ulcer and acute gastric mucosal
lesion, ulcer caused by a nonsteroidal anti-inflammatory
agent; hyperacidity and ulcer due to postoperative stress;
upper gastrointestinal hemorrhage due to invasive stress;
gastritis atrophicans after operation of endoscopic
demucosation against early gastric cancer; hyperplastic
polyp; idiopathic thrombocytopenic purpura; a disease due
to Helicobacter pylori; asthma due to gastric acid reflux,
sleep disorder due to gastric acid reflux; abdominal pain
due to GERD; Laryngitis; chronic obstructive pulmonary
disease (COPD); obstructive apneusis; and Barrett's
esophagus.
Incidentally, the term "an injectable composition" as
used herein means not only a final injectable solution, but
also an injectable composition precursor which can be
prepared into a final injectable solution with the use of a
dissolving solvent upon using [for example, a liquid
injectable composition (a concentrated or condensed
injectable composition) or a solid injectable composition
(such as a freeze-dried injectable composition)].
According to the present invention, there can be
provided a high-quality injectable composition in which
finely particulate insolubles are not formed when the
injectable composition is kept and supplied in a glass
container and even in a plastic container and also when the
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injectable solution prepared above is kept in these
containers for a long time.
Best Mode for Carrying Out the Invention
The injectable composition of the present invention
contains lansoprazole, its optically active compound or a
salt thereof and a chelating agent in a weight ratio of
about 0.03 o to about 67 0, preferably about 0.3 o to about
33 0, more preferably about 0.6 % to about 6.7 0 of the
chelating agent relative to lansoprazole, its optically
active compound or a salt thereof.
The salt of lansoprazole or its optically active
compound preferably includes a pharmaceutically acceptable
salt, for example, a salt with an inorganic. base, a salt
with an organic base, a salt with a basic amino acid and
the like.
As the preferred examples of the salt with an
inorganic base, there may be mentioned, for example, an
alkali metal salt such as a sodium salt and a potassium
salt; an alkaline earth metal salt such as a calcium salt
and a magnesium salt; and an ammonium salt, etc.
The preferred examples of the salt with an organic
base include, for example, a salt with an alkylamine (e. g.,
trimethylamine, triethylamine), a heterocyclic amine (e. g.,
pyridine, picoline), an alkanolamine (e. g., ethanolamine,
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diethanolamine, triethanolamine), dicyclohexylamine, N,N'-
dibenzylethylenediamine or the like.
The preferred examples of the salt with a basic amino
acid include, for example, a salt with arginine, lysine,
ornithine or the like.
Among these salts, the alkali metal salt or the
alkaline earth metal salt is preferable. In particular,
the sodium salt is preferable.
Lansoprazole, its optically active compound or a salt
thereof can be prepared by per se known methods, for
example, the methods described in JP 61-50978 A, USP
4,628,098, JP 10-195068 A, WO 98/21201 or methods based on
these methods. Incidentally, the optically active compound
can be obtained by an optical resolution method (e.g., a
fractional recrystallization method, a chiral column method,
a diastereomer method, a method with a microorganism or an
enzyme), an asymmetric oxidation method.
The chelating agent includes edetic acid, its salt, a
derivative thereof, phosphoric acid, its salt, citric acid,
its salt, and any agent similar thereto that is capable
preparing a complex compound with a metal ion. The salt
includes preferably a pharmacologically acceptable salt,
for example, a salt with inorganic base such as alkali
metal salt (e. g., sodium, potassium, etc.), an alkaline
earth metal salt (e. g., calcium, magnesium, etc.,),
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ammonium salt, etc. The salt also includes a salt with an
organic base, a basic amino acid, etc. In particular, a
sodium salt of edetic acid is preferable.
The container of the injectable composition includes a
5 glass container and a plastic container. As the plastic
container, there may be mentioned containers made of a
polyethylene, a polypropylene, a copolymer of polyethylene
and polypropylene, a polyvinyl chloride, a copolymer of
ethylene and vinyl acetate, a copolymer of ethylene and
10 propylene, silicone, a polybutadiene, a thermoplastic
elastomer, Teflon (Registered Trade Mark), a polyurethane,
a cyclic polyolefin, a polyolefin, etc.
The injectable composition of the present invention
can be produced by using lansoprazole, its optically active
15 compound or a salt thereof and about 0.01 to about 1
equivalent/L, preferably about 0.1 to about 0.6
equivalent/L, more preferably about 0.15 to about 0.25
equivalent/L of an aqueous strong alkali solution in a
ratio of about 1 to about 3 equivalent of the latter
20 relative to 1 mol of the former and by dissolving
lansoprazole, its optically active compound or a salt
thereof in the aqueous strong alkali solution. Thus, the
present invention also includes the injectable composition
obtained by this method. In this method, the aqueous
strong alkali solution may be an aqueous sodium hydroxide
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solution.
Thus, the injectable composition of the present
invention has a preventing effect from the formation of
insolubles even when the composition is kept as an
injectable solution in any container and supplied after the
injectable solution is prepared by adding a chelating agent.
Further, in the present invention, while a strong alkali is
added, the amount of the strong alkali to be used can be
decreased, and the solubility of lansoprazole, its
optically active compound or a salt thereof can be improved.
Thus, in the present invention, a pain and a local
irritation by injection is suppressed by preparing the
injectable composition by using lansoprazole, its optically
active compound or a salt thereof and a strong alkali in a
ratio of about 1 to about 3 equivalent of the latter
relative to a mol of the former without using a non-aqueous
solvent (or a water-soluble organic solvent). In addition,
solubility of the freeze-dried preparation in at least one
liquid selected from water for injection, infusion
solutions and nutrient infusions can be improved by
preparing a freeze-dried preparation by using lansoprazole,
its optically active compound or a salt thereof and a
strong alkali in a ratio of about 1 to about 3 equivalent
of the latter relative to one mol of the former without
using a non-aqueous solvent (or a water-soluble organic
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solvent).
The injectable composition of the present invention
may further contain N-methylglucamine (meglumine). The
content of the "N-methylglucamine" is about 0.1 mg to about
1 mg, preferably about 0.1 to about 0.8 mg relative to 1 mg
of lansoprazole, its optically active compound or a salt
thereof.
The lowering of pH can be prevented by addition of N-
methylglucamine because of buffer action of N
methylglucamine, thereby preventing deterioration of the
quality of a preparation due to precipitation of impurities.
Further, by incorporating N-methylglucamine, such a high pH
can be maintained as about 9 to about 11, and further, as
about 8 to about 11 can be retained depending on the
concentration.
The "injectable composition" of the present invention
may further contain a saccharide. As the "saccharide",
there may be mentioned, for example, a monosaccharide (e. g.,
glucose, galactose, ribose, xylose, mannose, maltotriose,
maltotetraose, etc.), a disaccharide (e. g., sucrose,
lactose, cellobiose, trehalose, maltose, etc.), a
trisaccharide (e. g., raffinose, etc.), a sugar alcohol
(e.g., sorbitol, inositol, mannitol, etc.), a
polysaccharide (e. g., dextran, chondroitin sulfate,
hyaluronic acid, dextrin sulfate, etc.) and a salt thereof
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23
(e. g., sodium chondroitin sulfate, sodium hyaluronate,
etc.), a cyclic saccharide (e. g., cyclodextrin, branched
cyclodextrin, etc.). Of these saccharides, a sugar alcohol
is preferred. Mannitol is particularly preferred.
The amount of the "saccharide" to be added is about
0.1 to 20 mg, preferably about 0.5 to about 10 mg (e. g.,
about 1 to about 10 mg) relative to 1 mg of lansoprazole,
its optically active compound or a salt thereof.
The injectable composition of the present invention
may further contain additive(s). The "additive" includes,
as a pH regulator, for example, a water-soluble inorganic
acid (e. g., hydrochloric acid, sulfuric acid, carbonic acid,
phosphoric acid, etc.), an alkali metal salt of a water-
soluble inorganic acid (e. g., sodium chloride, potassium
chloride, sodium sulfate, potassium sulfate, etc.), an
alkaline earth metal salt of a water-soluble inorganic acid
(e.g., calcium chloride, magnesium chloride, etc.), a
water-soluble organic acid (e. g., citric acid, tartaric
acid, lactic acid, succinic acid, malic acid, acetic acid,
oxalic acid, benzoic acid, tannic acid, gluconic acid,
fumaric acid, sorbic acid, erysorbic acid, mesylic acid,
mefenamic acid, etc.), an alkali metal salt of a water-
soluble organic acid (e. g., sodium citrate, sodium tartrate,
etc.), an alkaline earth metal salt of a water-soluble
organic acid (e. g., calcium citrate, calcium lactate,
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magnesium gluconate, etc.), a neutral amino acid (e. g.,
glycine, alanine, etc.), an acidic amino acid (e. g.,
aspartic acid, glutamic acid, etc.), a salt of an acidic
amino acid (e. g., sodium aspartate, potassium glutamate,
etc.), a salt of a basic amino acid (e. g., lysine
hydrochloride, arginine hydrochloride, etc.).
Moreover, if necessary, in the ~~injectable
composition" of the present invention, there may be
employed a buffer (e. g., sodium dihydrogenphosphate,
disodium hydrogenphosphate, etc.), an isotonizing agent
(e. g., glucose, sodium chloride, etc.), a stabilizer (e. g.,
sodium hydrogensulfite, etc.), a soothing agent (e. g.,
glucose, benzyl alcohol, mepivacaine hydrochloride,
xylocaine hydrochloride, procaine hydrochloride, carbocaine
hydrochloride, etc.), a preservative (e. g., p-oxybenzoate
such as methyl p-oxybenzoate and propyl p-oxybenzoate,
thymelosal, chlorobutanol, benzyl alcohol, etc.).
Examples of the injectable composition of the present
invention include an injectable composition comprising
lansoprazole, its optically active compound or a salt
thereof, a chelating agent, a strong alkali (e.g., an
alkali metal hydroxide such as sodium hydroxide, etc.), N-
methylglucamine and a saccharide. The preferred injectable
composition includes an injectable composition comprising
lansoprazole, its optically active compound or a salt
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thereof, sodium hydroxide, an edetate, N-methylglucamine
and mannitol. In such an injectable composition, the
amount of each component may be about 0.009 mg to about
20.1 mg of one of disodium edetate, tetrasodium edetate and
5 calcium disodium edetate or a combination thereof, about 8
mg to about 24 mg of N-methylglucamine, about 50 mg to
about 70 mg of a sugar alcohol (e.g., mannitol, etc.) and
about 3 mg to about 10 mg of sodium hydroxide relative to
mg of lansoprazole, its optically active compound or a
10 salt thereof. The edetate may be separately filled in a
different container and mixed with the other components at
the time of using the composition.
The injectable composition of the present invention
may be in a liquid form (e. g., in the form of an aqueous
15 injectable solution, etc.), or may be in a semi-solid form
(e.g., concentrated aqueous injectable composition) or in a
solid form. The preferred injectable composition of the
present invention is a freeze-dried preparation (a
lyophilized injectable composition). The injectable
20 composition of the present invention also includes an
injectable composition dissolved in or diluted with a
dissolving liquid or a diluting liquid, when it is used.
The injectable composition of the present invention is
adjusted to pH about 9 to about 12, when it is used.
25 The injectable composition of the present invention
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26
(in particular, a freeze-dried preparation) can be
dissolved in or diluted with a dissolving liquid or a
diluting liquid substantially free from a non-aqueous
solvent (e.g., a water-soluble organic solvent such as
propylene glycol, polyethylene glycol, etc.), for example,
water for injection such as distilled water for injection,
an infusion solution (e.g., an electrolyte liquid such as
physiological saline) to prepare the injectable solution
easily. Therefore, usually, the injectable composition of
the present invention is substantially free from a non-
aqueous solvent (e. g., a water-soluble organic solvent such
as propylene glycol and polyethylene glycol). Moreover, in
such an aqueous injectable composition (injectable
solution), the solubility of lansoprazole, its optically
active compound or a salt thereof is not deteriorated even
when the solvent is substantially water (e. g., distilled
water). Further, the injectable composition of the present
invention may be dissolved in a non-aqueous solution, if
necessary.
Incidentally, since an aqueous solution of N-
methylglucamine has a sufficient buffer capacity at pH of
about 9 to about 11, the lowering of pH of a solution
containing lansoprazole, its optically active compound or a
salt thereof can be suppressed during the production of the
injectable composition comprising lansoprazole, its
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optically active compound or a salt thereof and re-
dissolving the injectable composition, thereby preventing
the deterioration of its quality.
The injectable composition of the present invention
can be produced by dissolving lansoprazole, its optically
active compound or a salt thereof in an aqueous strong
alkali solution (e. g., an aqueous sodium hydroxide solution,
etc.), adding a chelating agent and filling the solution
into a vial or an ampoule, and if necessary, lyophilizing
the solution. When N-methylglucamine, a saccharide, an
additive, etc. are added, the injectable composition can be
obtained by dissolving lansoprazole, its optically active
compound or a salt thereof, the chelating agent, N-
methylglucamine, the saccharide and the additive etc. in an
aqueous strong alkali solution (e. g., an aqueous sodium
hydroxide solution, etc.) and filling the solution into a
vial or an ampoule, and if necessary, lyophilizing the
solution. The composition may be prepared by filling a
chelating agent in a different container.
The most preferred concentration of the "aqueous
strong alkali solution" is about 0.15 to about 0.25
equivalent/L. In other words, for example, when sodium
hydroxide is employed as the strong alkali, the
concentration of the "aqueous sodium hydroxide solution" is
about 0.15 to about 0.25 mol/L. When a strong alkali other
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than sodium hydroxide is employed as the strong alkali, the
injectable composition of the present invention can be also
produced according to the above method.
The "dissolving" of lansoprazole, its optically active
compound or a salt thereof in an aqueous strong alkali
solution may be carried out by per se known methods.
The "freeze-drying (lyophilization)" may be carried
out by per se known methods, and is desirably carried out
by freezing a solution at a temperature of not higher than
-25°C, and drying the resultant with elevating the shelf
temperature to 25 to 40°C while retaining a vacuum degree
of a drying oven at a pressure of not more than about 13.3
Pa, in general.
As the "glass container (vial)", one made of a glass
usable for an injectable composition is preferred. The
preferred "vial" is USP TYPE I, II, III or the like,
particularly TYPE I. Moreover, such a glass vial that
decreases the amount to be eluted of an alkali more than
usual.
Further, a plastic vial such as a vial made from a
cyclic polyolefin [e. g., CZ vial manufactured by Daikyo
Seiko, Ltd.] is also employed.
The configuration and the size of the vial are not
specifically limited. The capacity of the vial is
preferably not more than 100 mL, more preferably not more
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than 40 mL, and particularly not more than 20 mL. The
typical examples of vials include, for example, 17P vial,
9P vial, 5P vial, and 3.5P vial.
When an "ampoule" is used, as the glass container, one
made of a glass usable for an injectable composition is
preferred, and as the plastic container, one made of a
polyethylene, a polypropylene, a copolymer of polyethylene
and a polypropylene, a polyvinyl chloride, a copolymer of
ethylene and vinyl acetate, a copolymer of ethylene and
propylene, silicone, a polybutadiene, a thermoplastic
elastomer, Teflon (Registered Trade Mark), a polyurethane,
a cyclic polyolefin or a polyolefin can be used. The
configuration and the size of the ampoule are not
specifically limited. The capacity of the ampoule is
preferably not more than 30 mL, more preferably not more
than 20 mL, and particularly not more than 10 mL. The
typical examples of ampoule include, for example, lOP
ampoule, 5P ampoule, and 3P ampoule.
Further the injectable composition may be in the form
of a pre-filled syringe in which the injectable composition
is filled in advance.
A container of the injectable composition can be
coated with a packaging film. The packaging film is not
specifically limited and examples thereof include those of
cellophane, cellophane coated with vinylidene chloride,
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polyethylene, oriented polypropylene coated with
vinylidene chloride, nylon, oriented nylon, oriented nylon
coated with vinylidene chloride, oriented polypropylene,
non-oriented polypropylene, polyester, polyester coated
5 with vinylidene chloride, aluminum, ethylene-vinyl alcohol
polymer, etc. The packaging film may be transparent or
colored. Further, the packaging film may have a light
screening capability and may have a capability for
screening the composition from light of a specific
10 wavelength range which promotes photo-decomposition.
Preferable examples of such a film include that having a
capability for screening the composition from ultraviolet
light and visible light. The film material is not
specifically limited and may contain an ultraviolet
15 absorber. A light screening capability may be imparted by
paper. The packaging film may also have an oxygen barrier
capability and may contain an oxygen absorber. Further,
the packaging film may have heat resisting properties so
that it can be pasteurized or sterilized. Furthermore, the
20 film may have fine holes so as to enhance gas permeability,
wherein gas permeability may be adjusted by the film
thickness or the number of holes. The film may be adhered,
joined or bonded to a contained by means of heating,
adhesive, etc.
25 In case where the injectable composition of the
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present invention is a freeze-dried preparation and it
takes long time for the solution of the injectable
composition to become transparent due to vigorous foaming
of the contents upon re-dissolution, the re-dissolving time
can be reduced by using a vial or an ampoule coated with a
silicone. As the silicone to be used in coating, there may
be mentioned, a silicone oil such as a
poly(dimethylsiloxane), a poly(methylhydrogensiloxane); a
varnish silicone such as a methyl varnish silicone and a
methyl phenyl varnish silicone. As one example of the
preferred silicone, there may be mentioned KM-740
[manufactured by Shin-Etsu Chemical Co., Ltd.].
In the case where the injectable composition of the
present invention is that in an aqueous liquid form, the
injectable composition can be used by pulling out a
predetermined amount of the composition with an injection
syringe from a vial or an ampoule. In the case where the
injectable composition of the present invention is a
freeze-dried preparation, the preparation is utilized by
re-dissolving upon using.
As to the "solvent for re-dissolving", it is
unnecessary to employ a solution containing such a non-
aqueous solvent as might exhibit a toxicity when used in a
high concentration, such as polyethylene glycol, etc.
Examples of the solvent for re-dissolving include water for
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injection (distilled water for injection), an infusion
solution [an electrolyte solution (e. g., physiological
saline, a Ringer's solution, etc.), a nutrition infusion
solution (a carbohydrate solution, (e. g., a glucose
solution such as 50 (w/v) glucose solution, etc.), an
injectable solution of a protein amino acid, an injectable
solution of a vitamin, etc.), a blood substitute wherein an
electrolyte solution and a nutrition infusion solution
(e.g., a carbohydrate solution) are combined, a fat
emulsion wherein fats are emulsified, etc.], and a mixed
solvent of two or more kinds thereof . To the solvent may
be optionally added a pH-adjusting agent (e. g., an acidic
substance, a weak-alkaline substance, etc.). In this
connection, the injectable composition of the present
invention may be re-dissolved in an organic solvent such as
ethanol, propylene glycol and polyethylene glycol, and
after dissolving in the organic solvent, the injectable
composition may be further diluted with a solvent such as
that exemplified with respect to the above "solvent for re
dissolving".
The above "electrolyte solution" is a solution
obtained by dissolving an electrolyte in water for
injection, and includes, for example, a solution comprising
one or more kinds of sodium chloride, potassium chloride,
calcium chloride, sodium lactate, sodium
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dihydrogenphosphate, magnesium carbonate and the like, a
Ringer's solution of lactic acid, a Ringer's solution of
acetic acid, etc. The preferred electrolyte solution
includes a solution containing sodium chloride, in
particular, a physiological saline [0.9% (w/v) sodium
chloride solution].
The above "carbohydrate solution" is a solution
obtained by dissolving a saccharide in water for injection,
and includes, for example, a solution containing one or
more kinds of glucose, fructose, sorbitol, mannitol,
dextran and the like. The preferred carbohydrate solution
includes 5 to 700 (w/v) glucose solution, especially, 50
(w/v) glucose solution and l00 (w/v) glucose solution.
The above "injectable solution of a protein amino
acid" is a solution obtained by dissolving an amino acid in
water for injection, and includes, for example, a solution
containing one or more kinds of glycine, aspartic acid,
lysine and the like.
The above "injectable solution of a vitamin" is a
solution obtained by dissolving a vitamin in water for
injection, and includes, for example, a solution containing
one or more kinds of vitamin B1, vitamin C and the like.
Preferred example of "the solvent for re-dissolving"
includes water for injection, physiological saline, and a
glucose solution (e. g., 5 % (w/v) glucose solution, etc.).
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Lansoprazole, its optically active compound or a salt
thereof has an excellent anti-ulcer action, gastric acid
secretion-inhibiting action, mucosa-protecting action,
anti-Helicobacter pylori action, etc., and is of low
toxicity.
The injectable composition of the present invention is
useful in mammals (e.g., human beings, non-humans such as
monkeys, sheep, bovines, horses, dogs, cats, rabbits, rats,
mice, etc.) for the treatment and prevention of
peptic(digestive) ulcer (gastric ulcer, duodenal ulcer,
stomal ulcer, acute stress ulcer); gastroesophageal reflux
disease [(GERD); reflux esophagitis, gastroesophageal
reflux disease not involving esophagitis (Symptomatic GERD),
etc.]; gastritis; Zollinger-Ellison syndrome (which is
often included in peptic ulcer); NUD (Non Ulcer Dyspepsia);
gastric cancer (inclusive of gastric cancer accompanied
with enhanced production of interleukin-1(3 due to genetic
polymorphism of interleukin-1); gastric MALT lymphoma;
upper gastrointestinal hemorrhage due to gastric ulcer,
duodenal ulcer, acute stress ulcer and acute gastric
mucosal lesion, ulcer caused by a nonsteroidal anti-
inflammatory agent [inclusive of ulcer due to Aspirin (low
dose for preventing heart disease)]; hyperacidity and ulcer
due to postoperative stress; upper gastrointestinal
hemorrhage due to invasive stress (stress from major
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surgery necessitating intensive management after surgery,
and from cerebral vascular disorder, head trauma, multiple
organ failure and extensive burn necessitating intensive
treatment); gastritis atrophicans after operation of
5 endoscopic demucosation against early gastric cancer;
hyperplastic polyp; idiopathic thrombocytopenic purpura; or
a disease due to Helicobacter pylori (NUD, GERD, gastritis
atrophicans after operation of endoscopic demucosation
against early gastric cancer, hyperplastic polyp,
10 idiopathic thrombocytopenic purpura, iron-deficiency anemia,
chronic urticaria, Raynaud's phenomenon, ischemic heart
disease, migraine headache, Guillan-Barre' sydrome, etc.
due to Helicobacter pylori); asthma due to gastric acid
reflux, sleep disorder due to gastric acid reflux,
15 abdominal pain due to GERD; laryngitis; chronic obstructive
pulmonary disease (COPD); obstructive apneusis; and
Barrett's esophagus. Particularly, the composition is
useful for the treatment of gastroesophageal reflux disease
(GERD); gastric ulcer, duodenal ulcer, acute stress ulcer
20 and acute gastric mucosal lesion, etc. each of which
involves haemorrhagia which is impossible to be treated by
oral administration. Further, the injectable composition
of the present invention is also useful for Helicobacter
pylori eradication; suppression of the above-mentioned
25 upper gastrointestinal hemorrhage; treatment and prevention
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of hyperacidity and ulcer due to postoperative stress; pre-
anesthetic administration etc. Particularly, the
composition is useful for the treatment of gastroesophageal
reflux disease (GERD); gastric ulcer, duodenal ulcer, acute
stress ulcer and acute gastric mucosal lesion, etc. each of
which involves haemorrhagia which is impossible to be
treated by oral administration of lansoprazole, its optical
active compound or a salt thereof. Further, the
composition is also useful for the prevention and treatment
of gastroesophageal reflux disease (GERD). The injectable
composition of the present invention can be administered
parenterally (e. g., drip administration, intravenous
administration, intramuscular administration, subcutaneous
administration) for treating or preventing these diseases.
In case the injectable composition of the present invention
is parenterally administered to the subject to whom oral
administration cannot be applied because of hemorrhage, the
injectable composition of the present invention exhibits
superior effect of hemostasis by parenteral administration,
and once oral administration becomes possible, such
parenteral administration can be replaced by oral
administration.
Lansoprazole, its optically active ingredient or a
salt thereof which is the active ingredient in the
injectable composition of the present invention may be used
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in combination with other active ingredients (e.g., one to
three other active ingredients).
The "other active ingredients" include, for example,
substances having an anti-Helicobacter pylori action,
imidazole compounds, bismuth salts, quinolone compounds,
and so forth. Of these substances, preferred are
substances having an anti-Helicobacter pylori action,
imidazole compounds etc. The "substances having an anti-
Helicobacter pylori action" include, for example,
antibiotic penicillins (e. g., amoxicillin, benzylpenicillin,
piperacillin, mecillinam, etc.), antibiotic cefems (e. g.,
cefixime, cefaclor, etc.), antibiotic macrolides (e. g.,
antibiotic erythromycins such as erythromycin,
clarithromycin etc.), antibiotic tetracyclines (e. g.,
tetracycline, minocycline, streptomycin, etc.), antibiotic
aminoglycosides (e. g., gentamicin, amikacin, etc.),
imipenem, and so forth. Of these substances, preferred are
antibiotic penicillins, antibiotic macrolides etc. The
"imidazole compounds" include, for example, metronidazole,
miconazole, etc. The "bismuth salts" include, for example,
bismuth acetate, bismuth citrate, etc. The "quinolone
compounds" include, for example, ofloxacin, ciploxacin, etc.
In particular, it is preferred for Helicobacter pylori
eradication that the injectable composition of the present
invention is used in combination with antibiotic
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penicillins (e. g., amoxicillin) and/or antibiotic
erythromycins (e. g., clarithromycin).
The dose per day of Lansoprazole, its optically active
ingredient or a salt thereof which is the active ingredient
in the injectable composition of the present invention
varies depending on severity of symptom; age, distinction
of sex and weight of an administration subject; time and
interval of administration; species of active ingredients,
etc., and is not particularly limited. For example, the
dose per day is about 0.1 to about 2 mg/kg weight, and
preferably about 0.2 to about 1.5 mg/kg weight, based on
lansoprazole, its optically active compound or a salt
thereof which is the active ingredient, when parenterally
administered as a peptic anti-ulcer agent to an adult human
(60 kg). The injectable composition of the present
invention is administered once a day or dividedly twice to
thrice per day. The concentration of lansoprazole, its
optical active compound or a salt thereof in the injectable
composition to be administered is about 0.001 to about 40
mg/mL, preferably about 0.01 to about 30 mg/mL, and
particularly preferably about 0.03 to about 10 mg/mL.
The injectable composition of the present invention
has an excellent quality, in that the composition is free
from the formation of particulate insolubles in case where
the pharmaceutical composition containing lansoprazole
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which is a 2-[(2-pyridyl)methylsulfinyl]benzimidazole
compound, its optically active compound or a salt thereof
is filled, kept and supplied either in a glass container or
in a plastic container.
The following examples further illustrate the present
invention in detail but are not to be construed to limit
the scope of the invention.
As mannitol used in the following Examples, the one
that complies with the Japanese Pharmacopoeia, Fourteenth
Edition, European Pharmacopoeia and USP was used.
Example 1
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole;
hereinafter briefly referred to as Compound A) was promptly
dissolved in an aqueous sodium hydroxide solution (0.2
mol/L). To the solution were added mannitol, N-
methylglucamine and water for injection. After dissolution,
the resultant solution was subjected to sterile filtration
with a filter (0.22 Vim) made from Durapore (manufactured by
Nihon Millipore Ltd.). The solution thus obtained (2 mL)
was filled in a 17P vial (manufactured by Daiwa Special
Glass, Co., Ltd.) and freeze-dried to prepare a freeze-
dried injectable preparation containing Compound A (30 mg),
sodium hydroxide (3.45 mg), mannitol (60 mg) and N-
methylglucamine (10 mg) (hereinafter briefly referred to as
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Preparation A).
Preparation A was dissolved in a dissolving liquid as
shown in Table 1 (5 mL) to prepare the injectable solution
having the formulation as shown in Table 2. Each 5 mL
5 portion of the injectable solutions shown in Table 2 was
diluted with physiological saline (50 mL) in a infusion
container made of ethylene-propylene copolymer (0.9% Sodium
Chloride Injection USP manufactured by B.Braun Medical
Inc.). After dilution, the amounts of particulate
10 insolubles were measured in accordance with the Japanese
Pharmacopoeia, General Tests, Insoluble Particulate Matter
Test for Injection, Method 1, Light Obscuration Particle
Count Test. The results are shown in Table 3.
In a plastic container made of ethylene-propylene
15 copolymer used in U.S.A., an increase in formation of
particulates somewhat recognized in Preparation A, but the
formation of the particulates was suppressed by using
disodium edetate in a proportion of not less than 0.5 mg
relative to 30 mg of Compound A. The number of particles
20 was sufficiently lower as compared with the number that is
regulated in the Japanese pharmacopoeia that the number of
particles having a particle size of not less than 10 um is
not more than 6,000 and the number of particles having a
particle size of not less than 25 um is not more than 600
25 per one container. Thus, it was proved that the injectable
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41
composition of the present invention could be used in the
form of a plastic container.
Table 1
Dissolving 1 2 3 4 5
liquid
Disodium 0 mg 0.5 mg 1.0 mg 1.5 mg 5.0 mg
edetate
Water for 5 mL 5 mL 5 mL 5 mL 5 mL
injection
Table 2
Formulation 1 2 3 4 5
Compound A 30 mg 30 mg 30 mg 30 mg 30 mg
N-methylglucamine 10 mg 10 mg 10 mg 10 mg 10 mg
Mannitol 60 mg 60 mg 60 mg 60 mg 60 mg
Sodium hydroxide 3.45 3.45 3.45 3.45 3.45
mg mg mg mg mg
Disodium edetate 0 mg 0.5 mg 1.0 1.5 5.0 mg
mg mg
Water for 5 mL 5 mL 5 mL 5 mL 5 mL
injection
Table 3
Measured value of particulate
matter
(Number of particles
per container)
Particles having a Particles having a
particle size of not particle size of not
less than 10 ~m less than 25 um
Formulation 2024 18
1
Formulation 139 4
2
Formulation 128 0
3
Formulation 191 4
4
Formulation 209 0
5
Example 2
Compound A and disodium edetate were promptly
dissolved in an aqueous sodium hydroxide solution (0.2
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42
mol/L). To the solution were added mannitol, N-
methylglucamine and water for injection. After dissolution,
the resultant solution was subjected to sterile filtration
with a filter (0.22 um) made from Durapore (manufactured by
Nihon Millipore Ltd.). The solution thus obtained (2 mL)
was filled in a 17P vial (manufactured by Daiwa Special
Glass, Co., Ltd.) and freeze-dried to prepare a freeze-
dried injectable preparation as shown in Table 4.
The preparation shown in Table 4 was dissolved in
water for injection (5 mL) to prepare an injectable
preparation. The pH and the foreign insoluble matter of
each injectable preparation were measured in accordance
with the Japanese Pharmacopoeia, General Tests, Foreign
Insoluble Matter Test for Injection. The results are shown
in Table 5.
After dissolution of the preparation shown in Table 4
in water for injection (5 mL), the solution had pH about 11
and met the criteria of foreign insoluble matter provided
by the Japanese Pharmacopoeia, Injection. Thus, it was
proved that the injectable composition of the present
invention wherein disodium edetate was added was of good
quality as an injectable composition.
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Table 4
Formulation 1 2 3 4
Compound A 30 mg 30 mg 30 mg 30 mg
N-methylglucamine 10 mg 10 mg 10 mg 10 mg
Mannitol 60 mg 60 mg 60 mg 60 mg
Sodium hydroxide 3.70 mg 3.77 mg 3.82 mg 4.11 mg
Disodium edetate 1.0 mg 1.5 mg 1.5 mg 1.5 mg
Table 5
pH Foreign Insoluble Matter
Formulation 10.9 clear and free from foreign
1
insoluble matters that is clearly
detectable.
Formulation 10.9 clear and free from foreign
2
insoluble matters that is clearly
detectable.
Formulation 11.1 clear and free from foreign
3
insoluble matters that is clearly
detectable.
Formulation 11.3 clear and free from foreign
4
insoluble matters that is clearly
detectable.
Example 3
Compound A was promptly dissolved in an aqueous sodium
hydroxide solution (0.2 mol/L). To the solution were added
mannitol, N-methylglucamine and water for injection and the
mixture was dissolved. Then, disodium edetate was
dissolved in water for injection together with a small
amount of sodium hydroxide. Both solutions were mixed and
subjected to sterile filtration with a filter (0.22 um)
made from Durapore (manufactured by Nihon Millipore Ltd.).
The solution thus obtained (2 mL) was filled in a 17P vial
(manufactured by Daiwa Special Glass, Co., Ltd.) and
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freeze-dried to prepare a freeze-dried injectable
preparation as shown in Table 6.
After the freeze-dried injectable composition shown in
Table 6 was stored at 40°C and 75o RH for 3 months, the
composition was dissolved in physiological saline (5 mL) to
prepare the injectable solution as shown in Table 7. Each
injectable solution shown in Table 7 was diluted with
physiological saline (50 mL) in an infusion container made
of ethylene-propylene copolymer (0.9o Sodium Chloride
Injection USP manufactured by B.Braun Medical Inc.). After
dilution, the amounts of particulate insolubles were
measured in accordance with the Japanese Pharmacopoeia,
General Tests, Insoluble Particulate Matter Test for
Injection, Method 1, Light Obscuration Particle Count Test.
The results are shown in Table 8.
In a plastic container made of ethylene-propylene
copolymer used in U.S.A., an increase in formation of
particulates somewhat recognized in Formulation 1
(corresponding to Preparation A), but the formation of the
particulates was suppressed by using disodium edetate in a
proportion of not less than 1.0 mg relative to 30 mg of
Compound A. The number of particles was sufficiently lower
as compared with the number that is regulated in the
Japanese pharmacopoeia that the number of particles having
a particle size of not less than 10 um is not more than
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6,000 and the number of particles having a particle size of
not less than 25 um is not more than 600 per one container.
Thus, it was proved that the injectable composition of the
present invention could be used in the form of a plastic
5 container.
Table 6
Formulation 1 2 3 4 5
Compound A 30 mg 30 mg 30 mg 30 mg 30 mg
N-methylglucamine 10 mg 10 mg 10 mg 10 mg 10 mg
Mannitol 60 mg 60 mg 60 mg 60 mg 60 mg
Sodium hydroxide 3.45 3.77 3.81 4.30 6.93
mg mg mg mg mg
Disodium edetate 0 mg 1.0 mg 1.5 3.0 mg 15.0
mg mg
Table 7
Formulation 1 2 3 4 5
Compound A 30 mg 30 mg 30 mg 30 mg 30 mg
N-methylglucamine 10 mg 10 mg 10 mg 10 mg 10 mg
Mannitol 60 mg 60 mg 60 mg 60 mg 60 mg
Sodium hydroxide 3.45 3.77 3.81 4.30 6.93
mg mg mg mg mg
Disodium edetate 0 mg 1.0 mg 1.5 3.0 mg 15.0
mg mg
Water for 5 mL 5 mL 5 mL 5 mL 5 mL
injection
10 Table 8
Measured value of particulate
matter
(Number of particles
per container)
Particles having a Particles having a
particle size of not particle size of not
less than 10 um less than 25 um
Formulation 2704 71
1
Formulation 37 1
2
Formulation 130 2
3
Formulation 47 1
4
Formulation 70 ~ 0
5
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Industrial Applicability
The injectable composition of the present invention,
which contains lansoprazole useful as an anti-ulcer agent,
its optically active compound or a salt thereof, can be
provided as an injectable composition having a high-quality
in that any particulate insolubles are not formed when the
injectable composition is kept and supplied in a glass
container and even in a plastic container.
